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Dipeptidyl Peptidase-4 Inhibition With Saxagliptin Enhanced Nitric Oxide Release and Reduced Blood Pressure and sICAM-1 Levels in Hypertensive Rats.
MedLine Citation:
PMID:  22932707     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
ABSTRACT:: Most patients with diabetes also have hypertension, a risk factor associated with atherothrombotic disease and characterized by endothelial cell (EC) dysfunction and loss of nitric oxide (NO) bioavailability. Recent studies suggest a possible antihypertensive effect with dipeptidyl peptidase-4 (DPP4) inhibition; however, the underlying mechanism is not understood. In this study, we tested the effects of the DPP4 inhibitor, saxagliptin, on EC function, blood pressure, and sICAM-1 levels in hypertensive rats. Spontaneously hypertensive (SH) rats were treated with vehicle or saxagliptin (10 mg/kg/day) for 8 weeks. NO and peroxynitrite (ONOO) release from aortic and glomerular ECs was stimulated with calcium ionophore and measured using electrochemical nanosensor technology. Changes in EC function were correlated with fasting glucose levels. Saxagliptin treatment was observed to increase aortic and glomerular NO release by 22% (p<0.001) and 23% (p<0.001), respectively, with comparable reductions in ONOO levels; the NO/ONOO ratio increased by >50% in both EC types (p<0.001) as compared to vehicle. Saxagliptin also reduced mean arterial pressure from 170 ± 10 to 158 ± 10 mmHg (p<0.001) and decreased sICAM-1 levels by 37% (p<0.01). The results of this study suggest that DPP4 inhibition reduces blood pressure and inflammation in hypertensive rats while increasing NO bioavailability.
Authors:
R Preston Mason; Robert F Jacob; Ruslan Kubant; Aleksander Ciszewski; J Jose Corbalan; Tadeusz Malinski
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-8-28
Journal Detail:
Title:  Journal of cardiovascular pharmacology     Volume:  -     ISSN:  1533-4023     ISO Abbreviation:  J. Cardiovasc. Pharmacol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-9-6     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7902492     Medline TA:  J Cardiovasc Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
*Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States †Elucida Research LLC, Beverly, MA, United States §Department of Biochemistry, Ohio University, Athens, OH, United States.
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